Parathyroid hormone production inhibitors containing vitamin d3 derivatives

ABSTRACT

An agent for suppressing the production of parathyroid hormone and a remedy for hyperparathyroidism containing a vitamin D 3  derivative described by the following general formula (1)  
                 
[in the formula, m is an integer of from 1 to 3, q is an integer of from 0 to 3, r is an integer of from 0 to 3 and X is carbon atom or oxygen atom, provided that 1≦q+r≦3] as an active ingredient.

TECHNICAL FIELD

This invention relates to parathyroid hormone (hereafter referred to as“PTH”) production inhibitors containing vitamin D₃ derivatives as theactive ingredient. The invention further relates to remedies forhyperparathyroidism containing vitamin D₃ derivatives as the activeingredient.

BACKGROUND ARTS

PTH is a polypeptide consisting of 84 amino acids and its main targetorgans are bone, cartilage and kidney. It is known that after bonding tothe receptor of a target cell, PTH starts various intra- andinter-cellular cascades such as the promotion of the production ofintracellular cyclic adenosine monophosphate (cAMP), the phosphorylationof intracellular proteins, the flow of calcium into a cell, thestimulation of the metabolic path of membrane phospholipids, theactivation of intracellular enzyme and the secretion of lysosome enzyme.It is also known that the expression of PTH gene is subjected tosuppressive control mainly with activated vitamin D₃ (Proc. Natl. Acad.Sci. U.S.A.), vol.89, pp. 8097-8101, 1992). It is reported that theabnormality in the production amount of PTH in vivo causes variousdiseases. Examples of the diseases are primary hyperparathyroidism andsecondary hyperparathyroidism accompanying to abnormal increase of PTHproduction.

The primary hyperparathyroidism is a systemic disease caused by theexcessive PTH secretion from one or more parathyroid glands and about90% of the patients are affected by parathyroid tumor. The secondaryhyperparathyroidism is a disease developed by the excessive secretion ofPTH caused by the metabolic disturbance of activated vitamin D, calciumand phosphorus of a patient of chronic renal failure resulting in thegrowth of parathyroid gland to exhibit resistance to1α,25-dihydroxyvitamin D₃ of physiological concentration and furtherprogress hyperplacia. There are many cases accompanying ostealgia andarthralgia owing to the increase of bone resorption by excessive PTH.Further, the disease sometimes develops symptoms other than bone partsuch as ectopic calcification of soft tissue and arterial wall caused byhypercalcemia and hyperphosphatemia.

The production mechanism of secondary hyperparathyroidism and thepathologic physiology of the parathyroid gland are being graduallycleared recently and the findings are influencing the therapeuticmethod. The possible production mechanisms of secondaryhyperparathyroidism are the trade-off theory, the activation disturbanceof vitamin D in the kidney, the resistance to 1α,25-dihydroxyvitamin D₃,the abnormality of sensitivity to calcium, the direct action ofphosphorus, etc.

The most important point among these factors is the accumulation ofphosphorus by the lowering of the renal function to increase the load ofphosphorus on the uriniferous tubule and inhibit the activity of1α-hydroxylase. The concentration of 1α,25-dihydroxyvitamin D₃ in serumis lowered by the continuation of the lowered state of renal function tocause hypocalcemic state by the calcium absorption disorder in smallintestines, etc., and the hyperphosphatemia according to the lowering ofphosphorus secretion from the kidney. Continuing hypocalcemia issupposed to promote the secretion of PTH and develop the secondaryhyperparathyroidism.

Accordingly, the preferable treatment for the secondaryhyperparathyroidism is the administration of a compound effective forsuppressing the secretion of PTH from parathyroid gland or a compoundhaving parathyroid cell proliferation suppressing action or theadministration of remedies effective for increasing a1α,25-dihydroxyvitamin D₃ receptor or calcium sensing receptor whichhave been confirmed to be lowered in the parathyroid cell. Knowncompounds having the above characteristics are 1α-hydroxyvitamin D₃ and1α,25-dihydroxyvitamin D₃ and these compounds are administered asremedies for the secondary hyperparathyroidism to achieve extremely higheffectiveness.

However, the number of 1α,25-dihydroxyvitamin D₃ receptor in theparathyroid gland is decreased in the patients with chronic renalinsufficiency administered with such activated vitamin D₃ preparationfor a long period and it has been difficult to suppress theproliferation of parathyroid cell and the hypersecretion of PTH by theadministration of the ordinary amount of activated vitamin D₃preparation.

Slatopolsky, et al. have succeeded in the suppression of PTH secretionfrom parathyroid gland by the intermittent intravenous injection of alarge amounts of 1α,25-dihydroxyvitamin D₃ (J. Clin. Invest., vol.74,pp. 2136-2143, 1984). This is known as activated vitamin D pulsetherapy.

As the theoretical basis of the therapy, it has been suggested thatactivated vitamin D₃ increases 1α,25-dihydroxyvitamin D₃ receptorlowered in the parathyroid gland of a patients with chronic renalinsufficiency (J. Clin. Invest. vol.86, pp. 1968-1975, 1990) andincreases calcium sensing receptor (Am. J. Physiol. vol.270, pp.F454-F460, 1996).

However, the activated vitamin D pulse therapy is liable to causehypercalcemia by the administration of a large amounts of1α,25-dihydroxyvitamin D₃ preparation. Accordingly, a 1α-hydroxyvitaminD₂ preparation (International Patent Application WO96/31215), a19-nor-1α,25-dihydroxyvitamin D₂ preparation (International PatentApplication WO97/02826) and a 22-oxa-1α,25-dihydroxyvitamin D₃preparation (Japanese Laid-open Patent Application (hereinafter referredto as JP-A) 3-7231) having calcium metabolic activities weaker than thatof the 1α,25-dihydroxyvitamin D₃ preparation are being used at presentas remedies for vitamin D-resistant secondary hyperparathyroidism.

Although these vitamin D₃ derivatives have weak calcium metabolicactivity compared with 1α,25-dihydroxyvitamin D₃, these derivativesstill remain weak activity which causes insufficient separation of PTHproduction suppressing action and calcium metabolic activity to oftencause hypercalcemia as a side action (Nephrol. Dial. Transport vol.11,pp. 121-129, 1996). Therefore, it is hard to say from the viewpoint ofside effects that the therapy using these preparations is sufficientlysatisfactory. Accordingly, more effective therapeutic effect isexpectable by a medicine which strongly suppresses PTH secretion withoutcausing hypercalcemia.

The vitamin D₃ derivative to be used in the present invention can besynthesized by the methods described in the International Patentapplication WO96/33716 and the International Patent ApplicationWO00/24712. These compounds are known to have bone resorption inhibitingactivity and osteogenesis promoting activity (International PatentApplication WO95/33716) and neutrophil infiltration suppressing activity(International Patent Application WO00/24712). Furthermore, thespecification of the JP-A 11-35470 discloses that the derivative has PTHproduction promoting activity.

DISCLOSURE OF THE INVENTION

The purpose of the present invention is to provide a PTH productionsuppressing agent free from actions to increase the calciumconcentration in the serum. Another purpose of the present invention isto provide remedies for hyperparathyroidism free from actions toincrease the calcium concentration in the serum.

The purposes of the present invention can be achieved by a PTHproduction suppressing agent containing a vitamin D₃ derivativeexpressed by the following general formula (1)

[in the formula, m is an integer of from 1 to 3, q is an integer of from0 to 3, r is an integer of from 0 to 3 and X is carbon atom or oxygenatom, provided that 1≦q+r≦3] as an active ingredient. Further, thepurpose is achieved by the use of the PTH production suppressing agentas a remedy for diseases caused by the promotion of PTH production,especially hyperparathyroidism.

The specification of the present invention describes that thesecompounds can strongly suppress the increased blood PTH level of vitaminD deficient animals without influencing the serum calcium level. Theresult seems to have contradiction with the PTH production promotingeffect described in the abovementioned JP-A 11-35470, however, thecontradiction can be explained as follows.

The vitamin D₃ derivative used in the present invention has bothantagonistic action and agonistic action and, in the specification ofJP-A 11-35470, the vitamin D₃ derivative used in the present inventiondeveloped the antagonistic action and promoted the production of PTHbecause the experiment in the specification was carried out by usingnormal mouse administered with 1α,25-dihydroxyvitamin D₃. Contrary, theexperimental system of the present invention used a vitamin D deficientanimal free from 1α,25-dihydroxyvitamin D₃ and, accordingly, the vitaminD₃ derivative of the present invention developed agonistic action tosuppress the production of PTH.

Since the physiological state of a patient of hyperparathyroidism issimilar to that of a vitamin D deficient animal, the vitamin D₃derivative of the present invention is useful as a remedy forhyperparathyroidism. The antagonistic action of the vitamin D₃derivative of the present invention is described also in thespecifications of JP-A 11-5787 and International Patent ApplicationWO00/24712.

BEST MODE FOR CARRYING OUT THE INVENTION

Among the vitamin D₃ derivatives expressed by the above formula (1) andused in the present invention, preferable derivatives are those of theformula wherein the term m is 1 or 2. The preferable combinations of theterms m, q, r and X are described in the Table 1 and the compounds ofNo.11, 13, 16, 21, 23 and 26 are especially preferable. When thecompound in the Table contains asymmetric carbon atom in the structure,the compound include both of (S) configuration and (R) configurationunless otherwise mentioned. TABLE 1 Compound No. m q r X 11 1 0 1 Oxygenatom 12 1 1 1 Oxygen atom 13 1 0 1 Carbon atom 14 1 0 2 Carbon atom 15 10 3 Carbon atom 16 1 1 0 Carbon atom 17 1 2 0 Carbon atom 18 1 3 0Carbon atom 21 2 0 1 Oxygen atom 22 2 1 1 Oxygen atom 23 2 0 1 Carbonatom 24 2 0 2 Carbon atom 25 2 0 3 Carbon atom 26 2 1 0 Carbon atom 27 22 0 Carbon atom 28 2 3 0 Carbon atom

The hyperparathyroidism is e.g. primary or secondary hyperparathyroidismcaused by the promotion of PTH production.

A PTH production suppressing agent or a remedy for hyperparathyroidismcontaining the above compound as an active ingredient can be prepared inthe form of pharmaceutical preparation by using the compound as anactive ingredient and forming in the form of a peroral agent or aninjection such as soft capsule, hard capsule, tablet and syrup byconventional method using a proper excipient. In the case ofadministering the compound once or plural times a day as an agent forsuppressing the production of PTH or a remedy for hyperparathyroidism,it is preferable to use the compound as a peroral agent. An injectioncapable of achieving temporarily high blood concentration is preferablefor a pulse therapy using the compound as a PTH production suppressingagent or a remedy for hyperthyroidism.

The excipient to be used in the present invention for a liquid agent ora parenteral agent is, for example, vegetable oils, mineral oils, whitepetrolatum, branched-chain fats or oils and high-molecular weightalcohols. Preferable excipients among the above substances are, forexample, vegetable oils such as cottonseed oil, corn oil, coconut oiland almond oil, especially preferably triglyceride of a medium-chainfatty acid.

Examples of preferable excipients for solid agent are cellulosederivatives such as crystalline cellulose, hydroxypropylcellulose,hydroxypropyl methylcellulose and methyl cellulose, polyvinylpyrrolidone, dextrin, cyclodextrin, casein, lactose, mannitol andgelatin.

The amount of the active ingredient in the suppressing agent or theremedy of the present invention is determined according to the state ofthe disease and is generally from 0.00004 to 0.2% by weight, preferablyfrom 0.0001 to 0.1% by weight.

The administration dose of the active ingredient is also dependent uponthe state of the disease and it is generally from 0.1 to 1,000μg/day/head, preferably from 1 to 100 μg/day/head or thereabout. Thedosing frequency is usually once to thrice per day. The pharmaceuticalpreparation is preferably prepared in a manner to satisfy the aboveconditions.

The usefulness of the present invention has been shown, as describedconcretely in the Examples, by experiments using rats having promotedPTH secretion in a vitamin D deficient state. Namely, it has been foundthat the PTH concentration in serum rapidly decreases by theadministration of the vitamin D₃ derivative shown by the above formula(1) (compound 11 (23S isomer)) to a vitamin D deficient rat.

The blood calcium level increasing activity of the vitamin D₃ derivativeexpressed by the above formula (1) (compound 11 (23S isomer)) is about1/377 compared with 1α,25-dihydroxyvitamin D₃ revealing extremely weakactivity of the derivative. Accordingly, the separation of theconcentration to suppress the production of PTH from the concentrationto develop the blood calcium level increasing action is realized in thevitamin D₃ derivative expressed by the above formula (1) and there is nodevelopment of hypercalcemia by the use of the derivative in contrastwith conventional vitamin D preparation.

It is concluded from the above results that the vitamin D₃ derivativesexpressed by the above formula (1) are useful as a PTH productionsuppressing agent and a remedy for hyperparathyroidism.

EXAMPLES Example 1

Action of (23S)-25-dehydro-1α,25-dihydroxyvitamin D₃-26,23-lactone(Compound No.11 (23S Isomer) on the Production of PTH in Vitamin DDeficient Rat with Time

(1) Male Wistar rats of 4 weeks old were purchased from Japan SLC (SLC,Shizuoka prefecture). The rats were put into wire cages three for eachcage and bred under the condition of 23±1° C. and 55±10% humidity byallowing the rats to free ingestion of a vitamin D deficient feed foranimal breeding (Ca, 0.0036%; P, 0.3%; Harlan Teklad Research Diet,Madison, Wis., U.S.A.) and drinking water (well water treated with0.4%±0.2 ppm hypochlorite) for 7 weeks. The number of animals were fivefor one group.

(2) As shown in the Table 2, the negative control group (Group 1) wasadministered with a solvent (5% ethanol/0.1% Triton X-100/physiologicalsaline solution) and the positive control group (Group 2) wasadministered with 0.5 μg/kg of 1α,25-dihydroxyvitamin D₃ by intravenousadministration.

(3) As the group administered with the vitamin D₃ derivative, the group(Group 3) was administered with the compound 11 (23S isomer) at a doseof 50 μg/kg by intravenous administration. The volume of administeredliquid was 2 mL/kg.

(4) The blood was collected from the descending abdominal aorta underanesthesia with ether 4, 8, 24, 48 and 72 hours after administration,serum was separated by the established method and the PTH concentrationand the calcium concentrations in the serum were measured. Themeasurement of PTH concentration was carried out by using theradioimmunoassay kit for the measurement of rat PTH produced byImmutopics(San C A.), and the calcium concentration was measured by theOCPC method (Am. J. Clin. Pathol), vol.45, pp. 290-296, 1966) using theType-7070 automatic analyzer manufactured by Hitachi, Ltd.

(5) The results are shown in the Table 2. TABLE 2 Change of PTHconcentration and calcium concentration in serum with time after theadministration of the Compound 11 (23S isomer) to vitamin D deficientrats PTH Calcium Administration conc. conc. Rate Time (pg/ml (mg/100 mlGroup Compound (mg/kg) (hrs) serum) serum) 1 Solvent — 0 512 ± 46  4.93± 0.12 (negative control) 2 1α,25- 0.5 4 458 ± 38   5.33 ± 0.09*dihydroxy- 0.5 8  399 ± 2***    6.00 ± 0.17*** vitamin D₃ 0.5 24   325 ±31***    5.87 ± 0.22*** (positive 0.5 48 488 ± 43    5.48 ± 0.15**control) 0.5 72 555 ± 67  5.10 ± 0.18 3 Compound 50 4   354 ± 65*** 5.03± 0.13 11 50 8   330 ± 72***   5.53 ± 0.12** (23S isomer) 50 24  319 ±1*** 4.82 ± 0.18 50 48  436 ± 51** 4.74 ± 0.13 50 72 528 ± 38  4.88 ±0.20 Normal rat of — — 56 ± 17 10.21 ± 0.06  same week oldThe experimental results are shown by the mean ± standard error (thenumber of experiments n = 5).The statistical significance test of the experimental data was carriedout by the Dunnet method and significant difference to the negativecontrol group was obtained at a significance level of *p < 0.05, **p <0.01 and ***p < 0.001.

The intravenous administration of 1α,25-dihydroxyvitamin D₃ at a dose of0.5 μg/kg showed the lowering of the PTH concentration in serum as earlyas 4 hours after the administration of 1α,25-dihydroxyvitamin D₃, andthe concentration was gradually lowered after 8 hours and 24 hours andshowed the lowest level after 24 hours. The level was graduallyincreased from the lowest level after 48 hours and 72 hours and returnedto the concentration comparable to that of the negative control group(Group 1) after 72 hours.

The change of the calcium concentration in serum with time wascompletely adverse to that of the PHT concentration. The calciumconcentration in serum began to increase as early as 4 hours after theadministration of 1α,25-dihydroxyvitamin D₃, reached the maximum levelafter 8 hours, gradually lowered thereafter and returned to nearly thesame level as the negative control group (Group 1) 72 hours after theadministration.

On the other hand, the intravenous administration of the compound 11(23S isomer) at a dose of 50 μg/kg significantly lowered the PTHconcentration in serum as early as 4 hours after the administration andthe concentration was lowered to the lowest level 24 hours after theadministration, gradually increased and returned to the level of thenegative control group after 72 hours. In this case, the calciumconcentration in serum was increased temporarily 8 hours after theadministration of the compound 11 (23S isomer) and was absolutely keptconstant at the other time. The increase of the serum calciumconcentration 8 hours after the administration is the result of theadministration of the compound 11 (23S isomer) at a dose of 50 μg/kg,and there was absolutely no increase of the serum calcium concentrationby the intravenous administration at a dose of 10 μg/kg and the PTHconcentration was significantly lowered at the dose.

Accordingly, it has been cleared that, in contrast with1α,25-dihydroxyvitamin D₃, the compound 11 (23S isomer) is effective forlowering the PTH concentration in serum without changing the calciumconcentration in serum.

Example 2

Change of Serum PTH Concentration and Serum Calcium Concentration ofVitamin D Deficient Rat 8 Hours After the Administration of(23S)-25-dehydro-1α-dihydroxyvitamin D₃-26,23-lactone (Compound No.11(23S Isomer) at Various Concentrations

(1) The experimental animals, the breeding conditions, etc., of theexperiment were similar to those of the Example 1.

(2) As shown in the Table 3, the negative control group (Group 1) wasadministered with a solvent (5% ethanol/0.1% Triton X-100/physiologicalsaline solution) and the positive control group (Group 2) wasadministered with 0.25 μg/kg of 1α,25-dihydroxyvitamin D₃ by intravenousadministration.

(3) As the group administered with the vitamin D₃ derivative, the group(Group 3) was administered with the compound 11 (23S isomer) at a doseof 2 μg/kg, 10 μg/kg and 50 μg/kg by intravenous administration. Thevolume of administered solution was 2 mL/kg.

(4) The blood was collected from the descending abdominal aorta underanesthesia with ether 8 hours after administration, serum was separatedby the established method and the PTH concentration and calciumconcentration in the serum were measured by the procedures similar tothose of the Example 1.

(5) The results are shown in the Table 3. TABLE 3 Change of serum PTHconcentration and serum calcium concentration of vitamin D deficientrats 8 hours after the administration of the Compound 11 (23S isomer) atvarious concentrations PTH Calcium Administration conc. conc. in serumRate Time (pg/ml (mg/100 ml Group Compound (mg/kg) (hrs) serum) serum) 1Solvent — 8 546 ± 35  4.67 ± 0.23 (negative control) 2 1α,25- 0.25 8 459± 14*    5.50 ± 0.17*** dihydroxy- vitamin D₃ (positive control) 3Compound 2 8 488 ± 47* 4.52 ± 0.18 11 10 8   385 ± 65*** 4.45 ± 0.05(23S isomer) 50 8   319 ± 56***  5.10 ± 0.10* Normal rat of — — 56 ± 1710.21 ± 0.06  same week oldThe experimental results are shown by the mean ± standard error (thenumber of experiments n = 5).The statistical significance test of the experimental data was carriedout by the Dunnet method and significant difference to the negativecontrol group was obtained at a significance level of *p < 0.05, **p <0.01 and ***p < 0.001.

The serum PTH concentrations of the group (Group 3) administered withthe compound 11 (23S isomer) were lowered depending upon theadministration dose by the administration at the dose of 2 μg/kg, 10μg/kg and 50 μg/kg compared with the negative control group (Group 1).It is known that 1α,25-dihydroxyvitamin D₃ also lowers dose-dependentlythe PTH concentration in serum and, in the present experiment, serum PTHconcentration was significantly lowered by the administration of1α,25-dihydroxyvitamin D₃ to the positive control group (Group 2). Theserum PTH concentration lowering action of the compound 11 (23S isomer)was judged from the results to be about {fraction (1/12)} of the actionof 1α,25-dihydroxyvitamin D₃. The characteristic feature of the compound11 (23S isomer) is the strong suppression of the PTH production at adose not to cause the increase of serum calcium concentration incontrast with 1α,25-dihydroxyvitamin D₃ which increases the serumcalcium concentration simultaneously with the lowering of the serum PTHconcentration.

Example 3

Calcium Metabolic Activity of Vitamin D Deficient Rats 8 Hours after theAdministration of (23S)-25-dehydro-1α,25-dihydroxyvitaminD₃-26,23-lactone (Compound No.11 (23S isomer)) at Various Concentrations

(1) The experimental animals, the breeding conditions, etc., of theexperiment were similar to those of the Example 1.

(2) As shown in the Table 4, the negative control group (Group 1) wasadministered with a solvent (5% ethanol/0.1% Triton X-100/physiologicalsaline solution) and the positive control group (Group 2) wasadministered with 1α,25-dihydroxyvitamin D₃ at a dose of 0.1 μg/kg, 0.5μg/kg and 2.5 μg/kg by intravenous administration.

(3) As the group administered with the vitamin D₃ derivative, the group(Group 3) was administered with the compound 11 (23S isomer) (Group 3)at a rate of 10 μg/kg, 50 μg/kg and 250 μg/kg by intravenousadministration. The volume of administered solution was 2 mL/kg.

(4) The blood was collected from the descending abdominal aorta underanesthesia with ether 8 hours after administration, serum was separatedby the established method and the calcium concentration in the serumwere measured by a procedure similar to the Example 1. The increase ofserum calcium concentration observed by the experiment shows the boneresorption activity.

(5) After collecting the blood from the descending abdominal aorta underanesthesia with ether 8 hours after administration, the duodenum wasextracted and the calcium absorption activity of the intestinal canalwas determined by inverted gut sac method described in the Am. J.Physiol., vol.216, pp. 1351-1359, 1969.

(6) The results are shown in the Table 4. TABLE 4 Calcium metabolicactivity of vitamin D deficient rats 8 hours after the administration ofthe Compound 11 (23S isomer) at various concentrations IntestinalCalcium Administration calcium conc. in serum Rate Time absorption(mg/100 ml Group Compound (mg/kg) (hrs) (pg/ml serum) serum) 1 Solvent —8 1.86 ± 0.08 4.73 ± 0.18 (negative control) 2 1α,25- 0.1 8    2.66 ±0.09***   5.30 ± 0.10** dihydroxy- 0.5 8    3.23 ± 0.24***    5.90 ±0.40*** vitamin D₃ 2.5 8    3.94 ± 0.43***    6.17 ± 0.07*** (positivecontrol) 3 Compound 10 8 1.89 ± 0.04 4.63 ± 0.09 11 50 8  2.32 ± 0.21*  5.43 ± 0.15** (23S isomer) 250 8    2.53 ± 0.10***    5.63 ± 0.07***The experimental results are shown by the mean ± standard error (thenumber of experiments n = 5).The statistical significance test of the experimental data was carriedout by the Dunnet method and significant difference to the negativecontrol group was obtained at a significance level of *p < 0.05, **p <0.01 and ***p < 0.001.

The intestinal calcium absorption promoting activity and serum calciumconcentration increasing activity, i.e. the bone resorption promotingactivity of the negative control group (Group 1) were dose-dependentlydeveloped by the administration of 1α,25-dihydroxyvitamin D₃ at a doseof from 0.1 μg/kg to 2.5 μg/kg. In contrast with the above case, theactivity was absolutely unobservable on the group (Group 3) administeredwith the compound 11 (23S isomer) at a dose of 10 μg/kg and weakintestinal calcium absorption promoting activity and serum calciumconcentration increasing activity, i.e. the bone resorption promotingactivity were observed at the administration dose of from 50 μg/kg to250 μg/kg. However, the activities were about 1/1,400 and 1/377,respectively, compared with 1α,25-dihydroxyvitamin D₃. Furthermore, theactivity caused by the compound 11 (23S isomer) was observable only at 8hours after the administration and was absolutely unobservable at 4hours and 24 hours after the administration. The result shows that thecalcium metabolism activity caused by the compound 11 (23S isomer) isextremely weak compared with 1α,25-dihydroxyvitamin D₃.

It has been cleared from the results of the Examples 1, 2 and 3 that thevitamin D₃ derivative to be used in the present invention suppresses thePTH synthesis in parathyroid gland and quickly lowers the PTHconcentration in serum without increasing the serum calciumconcentration. This finding shows the usefulness of the vitamin D₃derivative used in the present invention as a remedy forhyperparathyroidism caused by the promotion of PTH secretion.

Field of Industrial Utilization

The remedy containing a vitamin D₃ derivative as an active ingredientand provided by the present invention can be used as an agent forsuppressing the production of PTH or an agent for the treatment ofhyperparathyroidism. These PTH production suppressing agent andhyperparathyroidism treating agent can be administered for example as anorally administrable agent or an injection for pulse therapy.

1. An agent for suppressing the production of parathyroid hormonecontaining a vitamin D₃ derivative expressed by the following formula(1)

[in the formula, m is an integer of from 1 to 3, q is an integer of from0 to 3, r is an integer of from 0 to 3, and X is carbon atom or oxygenatom, provided that 1≦q+r≦3] as an active ingredient.
 2. A remedy forhyperparathyroidism containing the vitamin D₃ derivative expressed bythe above formula (1) as an active ingredient.
 3. A parathyroid hormoneproduction suppressing agent described in the claim 1 wherein m of theformula (1) is 1 or
 2. 4. A remedy for hyperparathyroidism described inthe claim 2 wherein m of the formula (1) is 1 or
 2. 5. A parathyroidhormone production suppressing agent described in the claim 1 wherein mof the formula (1) is 1, q is 0, r is 1 and X is oxygen atom.
 6. Aremedy for hyperparathyroidism described in the claim 2 wherein m of theformula (1) is 1, q is 0, r is 1 and X is oxygen atom.
 7. A parathyroidhormone production suppressing agent described in the claim 1 wherein mof the formula (1) is 1, q is 0, r is 1 and X is carbon atom.
 8. Aremedy for hyperparathyroidism described in the claim 2 wherein m of theformula (1) is 1, q is 0, r is 1 and X is carbon atom.
 9. A parathyroidhormone production suppressing agent described in the claim 1 wherein mof the formula (1) is 2, q is 0, r is 1 and X is oxygen atom.
 10. Aremedy for hyperparathyroidism described in the claim 2 wherein m of theformula (1) is 2, q is 0, r is 1 and X is oxygen atom.
 11. A parathyroidhormone production suppressing agent described in the claim 1 wherein mof the formula (1) is 1, q is 1, r is 0 and X is carbon atom.
 12. Aremedy for hyperparathyroidism described in the claim 2 wherein m of theformula (1) is 1, q is 1, r is 0 and X is carbon atom.